JPS6094963A - 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative expressed by formula I (X is halogen or NO2; either one of Y and Z is H and the other is halogen or NO2, provided that X and Y are not Cl at the same time; A and B are 1-6C straight chain or branched alkyl which may have alkoxyl group as a substituent group). EXAMPLE:Di(2-propoxyethyl) 4-( 2-fluoro-3-nitrophenyl )-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. USE:A hypotensive agent and vasodilator having a long duration of action. PREPARATION:An aldehyde compound expressed by formula II is reacted with an acetoacetic acid ester compound expressed by formula III and a 3-aminocrotonic acid ester compound expressed by formula IV to afford the aimed compound expressed by formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a 1,4-dihydropi-11dine-3,5-dicarboxylic acid diester derivative and a method for producing the same. More specifically, the present invention provides a blood pressure lowering effect.

The present invention relates to a 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative having excellent pharmacological effects such as vasodilatory action and long duration of action, and a method for producing the same.

Prior Art Conventionally, the formula 4-(0-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5 has been used as a compound having pharmacological effects such as hypotensive action and vasodilatory action. -dicarboxylic acid dimethyl ester (hereinafter abbreviated as nianidipine) is known. Although nifedipine is a compound that has excellent pharmacological effects such as hypotensive action, it has the disadvantage that its duration is short. Many Niezivin derivatives have been studied with the aim of obtaining compounds with pharmacological effects such as long-lasting hypotensive effects. For example, in Japanese Patent Publication No. 56-6417, 4-(
m-nitrophenyl) -2,6-cymethyl-1,4-
Dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-β-(N-benzyl-N-methylamino)ethyl ester hydrochloride (hereinafter abbreviated as nicardipine) has been reported. Also, in JP-A No. 55-9083:
is the 2'-nitrophenyl group at the 4-position of nifedipine,
2/, 3/,) Nianidipine derivatives converted to chlorophenyl groups have been reported.

Purpose of the invention The present inventors have discovered that the phenyl group at the 4-position of nifedipine is
．． A sheftyl 1,4-dihydropyridine-3,5-dicarboxylate derivative converted into a 5/-disubstituted phenyl group, etc. was synthesized. The present invention was achieved by discovering that the nifedipine derivative has strong pharmacological effects such as a strong hypotensive effect, and that the duration of the pharmacological effects is extremely long.

Therefore, an object of the present invention is to provide a novel 1,4-dihydrobi+1zine-3,5-dicarboxylic acid diester derivative that exhibits excellent pharmacological effects such as hypotensive action and has a long duration. be.

A further object of the present invention is to provide a novel method for producing 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivatives.

Structure and Effects of the Invention The compound provided by the present invention is a 1,4-dihydro-a-pyridine-3,5-dicarboxylic acid diester derivative represented by the following formula m.

The 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative of the present invention has the 4-dihydropyridine-3,5-dicarboxylic acid diester derivative at the 2' position.

It has a 3'-spanning 2/, 5/-disubstituted phenyl group, and is a novel substance that has not been specifically disclosed in the literature, and has long-lasting pharmacological effects such as hypotensive action. It is something that you have.

In the above formula [1], A and B are the same or different,
A linear or branched furkyl group or an alkoxy group is used as a purchasing group.1. represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Furkyl group is, for example, methyl, ethyl, n-propyl, isopropyl, n7
'Chill.

5ec-butyl, isobutyl groups, etc., and alkoxy groups such as methoxy, L-toxy, propoxy, impropoxy, butoxy, imbutoxy.

These include 5ec-butoxy and tert-butoxy groups.

X is a halogen atom or a nitro group, and examples of the halogen atom include a chlorine atom and a heptadon atom. Preferably it is a fluorine atom. Y and 2 represent a hydrogen atom, a halogen atom, or a di)O group, and either Y or z is a hydrogen atom and the other is a substituent other than a hydrogen atom. Also Y and X
cannot be a chlorine atom at the same time. Examples of the halogen atom include a chlorine atom and a fluorine atom.

Preferred examples of the 1,4-2hydropyridine-3,5-dicarboxylic acid diester derivative of the present invention are as follows.

(100) 2.6-dimethyl-4-(3-riOO”-
2'-fluorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-isopropyl ester
5-(2-methoxyethyl)ester (102) 2.6-dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-cy)-trobi11
Jin-3,5-dicarboxylic acid-3-methyl ester-5
-isopropyl ester (104) 2.6-dimethyl-4-(3'-riaa
-2'=fluorophenyl) -1,4-dihydropyridine-3,5-dicarphonic acid pyruester (106) 2,6-dimethyl-4-(3'-chloroa-
27-fluorophenyl)-,1,4-dihydrobiricin-3,5-dicarphonic acid di(2-methoxyethyl) ester (108) 2.6-dimethytL--4-(2'-fluoro a=3 '-Chloa-phenyl) -1,4-dihydrobi II Micin-3,5-dicarboxylic acid dimethyl ester (110) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1, 4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (112) 2,6-dimethyl-4- (2'-fluoro-a-3'-dithophenyl)-1,4-dihydro-a-pyridine-3,5- Dicarboxylic acid-3-methyl ester-5-
(2-n-propoxyethyl) ester (+14) 2,6-dimethyl-4- (2'-fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester −
5-ethyl ester (116) 2,6-dimethyl-4- (2'-fluof-3'-dito-a-phenyl) -1,4-dihydropyridine-3,5-dicarvone t11-3-aec-butyl ester-5 -isopropyl ester (118) 2,6-dimethyl-4(2/-fluoro-
3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3-8ee-butyl ester-5-n-propyl ester (120) 2,6-dimethyl-4- (2'-fluoro- □ 3'-ditrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diiso7゜robyldister (122) 2,6-dimethyl-4-(2'--yfluoro-3'-dimethyl aphenyl) -1,4-dihydro apiI cydine-3,5-dicarboxylic acid di(methoxyethyl)
Ester (124) 2,6-dimethyl-4- (2'-fluoro-3'-dithophenyl) -1,4-dihydrobi I
Idine-3,5-dicarboxylic acid di(ethoxyethyl) ester (126) 2,6-dimethyl-4-(2'-fluoro-3'-dithophenyl)-1,4-dihydropyridine-3,5-dicarvone Acid di(n-7'a boxyethyl) ester (12 g) 2,6-dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-cyhto.

Pyridine-3,5-dicarboxylic acid di(butodiethyl)
Ester (130) 2,6-dimethyl-4-(2'-fluoro-37-nitoe+phenylon-1,4-dihyde apyridine-3,5-dicarboxylic acid-3-methoxyethyl ester-5-ethoxyethyl Ester (132) 2,6-dimethyl-4-(2'-fluoro-37-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethoxyethyl ester-5-fi-propoxyethyl ester ( 134) 2,6-dimethyl-4-12'-fluoro-3'-di)o-phenyl)-1,4-dihydropyridine-3,5-dicarboxymethyl-n-propoxyethyl ester-5-8et-butoxyethyl ester (136 ) 2,6-dimethyl-4- (2'-fluoro-3'-nitocuphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5
-Methoxyethyl ester I Section 138) 2,6-dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-dihyde a pyridine-3,5-dicarpo/acid-3-t methyl ester- 5-Ethoxyethyl ester (14(1) 2,6-dimethyl-4 (2/-fluora-3'-nitrophenyl) -1,4-dishidoa-pyridine-3,5-dicarboxylic acid-3- n-propyl ester-5-n-propoxyethyl ester (142) 2,6-dimethyl-4- (2/-fluoro-37-nitoaphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3- sec-butyl ester/-35ec-butoxyethyl ester (144) 2,6-dimethyl-4-(2'-fluoro-3'-diphenyl)-1,4-dihydo-a pyridine-3,5-dicarboxylic acid -3-methyl ester-55e
c-Butoxyethyl ester (146) 2,6-dimethyl-4-(2'-fluora-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-.

-Propyl ester-5-rt-pentyloxyethyl ester (148) 2,6-dimethyl-4- (2'-fluoro-5'-nitrophenyl)-X,4-dihydro apiII
Dine-3,5-dicarboxylic acid di(methoxyethyl) ester (150) '2,6-dimethyl-4 (2/-fluora-5'-di)Cl phenyl) -1,4-dihyde apyridine-3,5 -dicarboxylic acid di(ethoxyethyl) ester (152) 2.6-dimethyl-4 (2/-fluoro-5'-ditoaphenyl)-'1. '4-dihydropyridine-3,5-dicarboxylic acid di(n-propoxyethyl) ester (154) 2,6-dimethyl-4 (2/-fluoro-5'-ditoe+phenyl) -1,4-dihydropyridine-3 , 5-dicarboxylic acid di(butoxyethyl) ester (156) 2,6-dimethyl-4 <2/-fluoro-5'-nitrophenyl) -1,4-dihyde a pyridine-3,5-dicarboxylic acid-3 -Methoxyethyl ester-5-ethoxyethyl ester (15B) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl)-1,4-:)human apyridine-3,5-dicarboxylic acid -3-Ethoxyethyl ester-5n 7'Cl poxyethyl ester (160) 2,6-dimethyl-4-=(2'-fluoro-5'-di-a-phenyl-1,4-dihydropyridine-3,5- dicarboxylic a-3-n-propoxyethyl ester-5-see-nodoxyethyl nitrile (162) 2.6-dimethyl-4-(2'-fluoro a
-5'-nitrophenyl) -1,4-dihydropyridine-3,5-dihluponic acid-3-methyl ester-5-
-x-=f-lester (164) 2.6-dimethyl-4-(2'-fluoro-5'-ditocuphenyl)-1
,4-dihydropyrodine-3,6-dicarboxylic acid-3-
Self-ee-butyl ester-5-isopropyl ester (166) 2,6-dimethyl-4- (2'-fluoro-5'-nitrophenyl) -1,4-dihydro L7 pyridine-3,5-dicarboxylic acid-3- sec-butyl ester-5-n-propyl ester (16B) 2,6-dimethyl-4~(2'-fluoro a
-57-ditrophenyl) 1.4-dihydropyridine-3,5-dicarboxylic acid ester (170) 2.6-dimethyl-4-(2'-fluoro-5'-nitrophenyl) -1 ,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-
Methoxyethyl ester (172) 2,6-dimethyl-4 (z/-fluora
-5'-nitrophenyl) -1,4-dihyde ◎Pyridine-3,5-dicarbonyl-3-ethyl ester-5
-Ethoxyethyl ester (174) 2,6-dimethyl-4 (2'-7-a-5'-nitrophenyl) -"1,4-dihydropyridine-3#5-dicarboxylic acid-3-n-propyl ester- 5-n-7' ey poxyethyl ester (176) 2,6-dimethyl-4-(2'-fluoro a
-5'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3-8ec-butylnisblue 5 5et-butoxyethyl ester (17B) 2,6-dimethyl-4-(2'-fluoro -5'-ditrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-511
cc-butoxyethyl ester (+80) 2,6-dimethyl-4-(2'-fluoro-5'-nitrophenyl) -1',4-dihydrobi I
797-3.5-dicarboxylic Ml 3 n-propyl ester-57n-pentyloxyethyl ester (182) 2.6-dimethyl-4-(2'-fluoro-3'-chlorophenyl)-1,4-dihydropyridine-3, 5-dicarboxylic acid di(methoxyethyl) ester (184) 2.6-dimethyl-4-(2'-fluoro-3'-chlorophenyl) -'1,4-dihydropyridine-3.5-dicarboxylic acid di(ethoxyethyl) Ester (186) 2,6-dimethyl-4-(2'-fluoro-3'-rio7z-nyl)-1,4-dihyde-a-pyridine-3,5-dicarboxylic acid di(n-propoxyethyl) Ester (188) 2.6-dimethyl-4-(2'-fluoro-3'-chlorophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid di(butoxyethyl) ester (190) 2.6- Dimethyl-4- (2'-fluoro-37-chloroa phenyl) -1,4-dihydra pyridine-3,5-dicarboxylic acid-3-methoxyethyl ester-5-ethoxyethyl ester (192) 2,6-dimethyl- 4-(2'-Fluo-a-3'-chlorophenyl)-1,4-dihydro-a-pyridine-3,5-dicarboxylic acid-3-ethoxyethyl ester-5nf lopoxyethyl ester (394) 2,6-dimethyl-4 -('2'-Fluo-a-3'-lya-rophenyl)-1,,s-dihyroviridine-3,5-dicarboxylic acid-3-n-butoxyethyl ester-5-sec-butoxyethyl Ester (196) 2.6-dimethyl-4-(2'--yluoro-3'-lyaa-phenyl)-1,4-dihyde b-pyridine-3.5-dib-luponic acid-3-methyl ester-5-
-R-ru ester (+98) 2,6-cymethyl-4
-(2'-fluoro-3'-ri110fenino I)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-11Iec-butyl ester-5-impropino 1 diester (200) 2,6-dimethyl-4-, (2/-)/
l-olor-3'-chlorophenyl)-+, 4-dihydropyridine-3,5-dicarboxylic acid-3-8ee-methyl ester = sn-propyl ester (202) 2,6-dimethyl-4-(2'-fluoro -37-tytyphenyl) -1,4-dihydropyridine-3,5-cycara! 2,6-dimethyl-4-(2'-fulme-3'-chlorophenyl)-1,4-dihydropyridine-3,5-dicarphonic acid-3-ethyl ester (204)
Ethoxyethyl ester (206) 2,6-dimethyl-4-(,2'-fluoro-a-3'-〃lorophenyl-1,4-dihydro-a-pyridi'-3,5-dicarboxylic acid-3-ethyl ester- 5-Ethoxyethyl ester (208) 2.6-dimethyl-4-(2'-fluoro a
-37-dihydroenyl) -1,4-dihyde a pyridine to 3,5-dicalfosom -3-n-pyrnist-Fl-n-p-a boxyethyl ester (210) 2,6-dimethyl- 4-(2'-fluoro-37-rioo phenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-sec-butyl ester-s-5ec-butoxyethyl ester (212) 2.6 -Dimemuru-4- (2'-fluoro-3'-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic 52-3-methyl ester-5
5ec-Butoxyethyl ester (214) 2.6-dimethousand-4-(2'-fluora-3'-rjrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-n-7 'CI pyl ester-1i n-pentyloxyethyl ester (216) 2,6-dimethyl-4-+5'-fluoro-2'-nitrophenyl)-1,4-dihydropyridine-3,5-di)J luponic acid -3-methyl ester-5-
Nithyl ester (218) 2,6-dimethyl-4
-(5'-fluoro-2'-nitrophenyl) -1,
4-dihydropyridine-3,5-dicarboxylic acid-3-s
ee 7'Tyl ester-5-isopropyl ester (220) 2,6-dimethyl-4-(5'-fluoro-2'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-sec- Butyl ester-5-n-propyl ester (222) 2.6-dimethyl-4-(5'-fluoro a
-2'-dihydropyridine-3,5-dicarbonyl diisopropyl ester (224) 2,6-cymethyl-4-(3'-fluoro-2'-nidocy7enyl) -1 ,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-methoxyethyl ester (226) 2.6-dimethyl-4-(3'--yluo-a-2'-nido-o-phenyl)71. 4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-
1-xyethyl ester (22B) 2,6-dimethyl-a (a/-fluoro-27-diphenyl)-1,,4-dihydropyridine-3,5-dicarboxylic acid-3-n-propyl ester-5 -n-propoxyethyl ester (230) 2,6-dimethyl-4 <37-fluoro-2'-nitrophenyl)-1,4-dihydropi11
Jin-3,5-dicarboxylic acid-3-sec-butyl ester-55ec-butotaka-ethyl ester (232) 2,6-dimethyl-4(3'-fluoro a-
2'-dihydro-a-phenyl)-1,4-dihydro-a-pyridine-
3,5-dicarboxylic acid-3-methyl ester-55ec
-7'Toxyethyl ester (234) 2.6-dimethyl-4=(3'-fluora-2'-dithophenyl), -1,4-dihydropyridine-3,5-dicarboxylic acid- 3-n-propyl ester-5-n-pentyloxyethyl ester (236) 2,6-dimethyl-4- (3'-fluora-2'-chlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid Di(methoxyethyl) ester (238) 2,6-dimethyl-4-(3'-fluoro a
-2'-lylorophenyl)-1,4-dihydropyridine-3,5-dicarphonic acid di(ethoxyethyl) ester (240) 2,6-dimethyl-4-('3'-fluoro2'-chlorophenyl) -1, 4-dihydropyridine-3,5-dicarboxylic di(n-7Poboxyethyl) ester (242) 2.6-dimethyl-4-'(3'-fluora-2'-chloroe+phenyl)-1,4-dihydro Pyricine-3,5-dicalphone Ml (n-ptoxyethyl)ester (244) 2,6-dimethyl-4-(3'-fluoro-27-cIa phenyl) -1,4-dihydropyridine-3,5-dicarvone Acid-3-methoxyethyl ester-5-ethoxyethyl ester (246) 2,6-dimethyl-4-(3'-fluoro-2'-riOe+ 7, =, ru) =, 1,4-dihydro a pyridine -3,5-dicarboxylic acid-3-ethoxyethyl ester -5-n-propoxyethyl ester (248) 2,6-dimethyl-4-(3'-fluoro-2'-rioophenyl)-5,4-dihydropyridine -3,5-dicarboxylic acid-3-n-propoxyethyl ester-5-1! ee-Butoxyethyl 7 Ter The 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative of the present invention has the following formula [■] IO [where x, y, and z are the same as defined above]. ] and the following formula [1■] CB, C0
CH,Coo-B ・・・・・・・・・・・・・・・［
111) [wherein B is the same as defined above. ] and the following formula [1V) NH,.

[In the formula, A is the same as defined above. ”3
- Manufactured by reacting with an amic acid ester compound.

To obtain the aldehyde compound of the above formula [1], the following formula (
V) can be easily produced by IC oxidation in the presence of a known oxidizing agent to produce Kl'J. Chromium is an oxidizing agent.

Examples include oxidizing agents containing elements such as silver and selenium.

The acetoacetic acid ester compound of the above formula ril) and the 3-amino/lytonic acid ester compound of the above formula rlV] can be easily produced by a known method.
wanamj et al., cbem, pharm, Bu
ll, vol. 27, 1426 (1979)].

When reacting the above-mentioned aldehyde compounds, γ-cetoacetic acid ester compounds, and 3-7 minocrotonic acid ester compounds, they may be used without a solvent, or in ethanol or propanol.

Low i furfurs such as impropatol, n-butanol, t-butanol; Ri I: Ia form.

In organic solvents such as halogenated hydrocarbons such as dichloroethane and torque el +1 ethane; aromatic compounds such as benzene and pyridine, 30 to 180'C1, preferably 50 to 1
The heating reaction is usually carried out at 50°C for 2 to 24 hours.

Aldehyde compound, acetoacetate compound, 3-7
The amount of minocrotonic acid ester used is 1 equivalent of the aldehyde compound! 0.8 to 1.5 and 0.8 to 1.5 equivalents can be used for #, respectively.

The 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative of the present invention has excellent pharmacological effects such as antihypertensive action, and its duration is also long. It is effective as a therapeutic agent for improving disorders and circulatory system diseases such as hypertension and ischemic heart disease. The present invention will be explained in more detail below with reference to Examples.

Reference example 1 2-fluore+ -3-nitrotoluene 3. o9' was added to 20 ml of ice-cooled acetic anhydride, and 4 ml of concentrated sulfuric acid was added dropwise. Anhydrous vinegar rf while keeping the temperature below l11'c.
l! 5 g of chromium trioxide dissolved in 20 ml was added in about 1 hour. After stirring for 2 hours, the reaction solution was poured into 1 s o mJ water, the resulting precipitate was separated, and the resulting solid was washed with 2% sodium bicarbonate solution. Dioxa 710 is added to the obtained solid.
4 mj of water and 0.4 mj of m sulfuric acid were added, and the mixture was heated under reflux for 30 minutes.

After removing the solvent and concentrating, it was extracted with CIIxC7t, and the organic fraction was collected, washed with water, and dried. Removal of the solvent yields the desired 2-fluoro-3-nitropenzaldehyde3.
0.9 was obtained.

Physical property values knee m, p,: 46 47°G IR (KBr) u"": 1 e 911.1 e
1o.

ax NMR (CDCj!,,) appm: 1n, 114(s
, IH) 8.56 to, B, I4 (m, 2H) 7.69-7.34 (m, 1) 1) Similar 2,3- and 2,5-disubstituted benzaldehyde compounds of K L, Tesen You can also get

Reference Example 2 20 ml of acetic anhydride was placed in a 200 ml three-necked flask and cooled on ice. To this, 73.09 (19.4 mmoj) of 2-fluoro-5-nide e+) was added, and 5.5 mm of concentrated sulfuric acid
ml was added dropwise little by little. Chromic anhydride g, o // (F+ 7.0'm
A solution (20 ml) of acetic anhydride (moj) was added dropwise over about 1 hour. After stirring for further Vc for 2 hours (~5-0),
The reaction solution was poured into 150 ml of ice water and extracted with CH*Cjt.

After washing the CH, (J, phase with water and drying with Na1SO4, the solvent was distilled off to give 2-fluoroQ-5-nitrobenzaldehyde sifcetylacetal as a pale yellow liquid with 4.23%
iil (15.6 mmoj, 80%) was obtained.

Physical property value IRu''-' (neat): 30 (+0.1754.
1528.1488°11x 1348.1190,1092.1056,1 (I46
,996NMRappm (CDCIJ: 8.48-
8.13 (m, 211), 7.88 (s
.

IH), 7.28 (dd, IH, J”9Hz)
, 2.13 (s, 68) above diacetylacetal derivative 4.02,9 (14,8 mmoJ) K dioxa 725 + nAI, 20 ml of H2O.

1 rd portion of concentrated sulfuric acid was added, and the mixture was heated under reflux for 30 minutes. The solvent was distilled off under reduced pressure and condensed.1. After that, add water, cH, c
The phase was washed with water, dried with NaSO4, and the solvent was distilled off. The yellow-orange liquid was purified by silica gel column chromatography to give pale yellow crystals. as 2-fluoro-5-dito a
Benzaldehyde is 1.96gL l 1.6mmoj
, 7o%) was obtained.

Physical property values m, p,: 59-600 IRt+”-(KBr): 1690, 1618, 152
4,1348ax 252 NMRδppm (CDCJ, ): 10.20 (s, I
H)', 8.77-8.32 (m, 2H), 7.4
2 (d<l, Ill, J=9Hz) Example 1 2-fluora-3-nitrobenzaldehyde 34o
mg (2,01 mmoj ) and acetovine vinegar! Add 940 m@(LOO+nma/) of 2-propoxyethyl to 2 tri K of ethanol, and add 7 m of 2-propoxyethyl and 0 m of water.
．． 5 ml was added and heated under reflux overnight. The residue obtained by distilling off the molten liquid was subjected to silica gel column chromatography (
CH,C/, : Ac0Et=10:1 3,5-dicarboxylic acid Z-(2-butoxyethyl) ester was produced as pale yellow crystals at 500 μm (0.98 rr).
vnol, 49'l) obtained leta.

Physical properties: 86-88゜ Bacterial H IRu (KBr): 1696, 1660.1528, 1
476ax 131i6, 1214.1112 NMR δppm (CDC/3): 7.8-7.4
(m, 2H), 7J-6,8 (m.

IH), 6.34 (8, IH), 5.20 (s, 11
(), 4.0 (m, 4H), 3.27 (t, 4B, J
+=6Hz), 2.23(s, 6H), 1.7-1
．． ．． 2 (m, 4H), 0.84 (t, 6H.

J=611z) Example 2 3-Rolo-2-fluorobenzaldehyde 318q(
2,n Ommol), acetoacetic acid-2-methoxyethyl tocostet 325ny (2,03mmol)
) and 3-7゛Isopvir atonate 2911
mg (2.03 mmoj) was added to 2 ml of isoprJ per-pal and heated under reflux for 10 hours. The solvent was distilled off and the residue was purified using silica gel column Iff column chromatography to obtain the target product, t-(3'-Cl0-2'-fluorophenyl)-2,6-dimethyl-1,4-dihydro-a-pyridine-3. ,5-dicarbo7M-3-isopropylester-5-(2-methoxyethyl)ester as pale yellow crystals 503Illlτ (1,18 mmoj,
Section 59) Obtained.

Physical property value knee 1y1. p,: 122124° side = 1 1RIJ (KBr): 1602.1488,145
4゜ax 1266.1200, 1102.101084N δp
pm (CDCJ, ): 7.2-6. ti (m,
3H), 6.35 (s.

18), 5.12(s, 111), 4.1
1 (m, IH), 4.1 (m.

2H), 3.5(m, 2H), 3.24(a, 3H
), 2.19(s, 6H) + 1.20(d
* 311 + J = 614 z ) , 1 , OO
(d, 3H, J = 6 Hz) At the same time 4- (3'-chloro-2'-fluorophenyl) -2,6-dimethyl-1,4-dihydropyridine-3,5-: 70 mg (0.17 mmoJ, 996),
4-(3'-chloroC1-2'7 fluorophenyl) -
2,6-dime+tL--1,4-dihydropyridine-3
,5-dicarboxylic acid di(2-methoxyethyl) ester IBI Ka110111C (0,11mmoJ, 6
%) obtained.

Physical properties of compound (5) Nizono-1 1Rt+ (KBr): 16g6,1492,1452
゜ax 1212.1098 NMRJppm1098N, ): 7.2-6.6
(m, 3H), 5. s 3 (s.

IH), 5.09 (s, IH), 4.8 (m, 2H)
, 2.21 (s, 6H), 1.20 (d, 6H, J=6
Hz), 1.00 (d, 6H, J-'6Hz) Compound (physical properties of Bl: m, p, : 156-1570 IRu (KBr): 1692, 1496, 1448° 1278.1202.1010 88Nδppm (CDCjl) Near, 2-6.6 (m,
3H), 5.92 (s.

1B), 5.13 (s, 111), 4.1 (m, 4H)
,a,5(m,4B),3.24(*,61(),2.
22(s,6B) Example 3 2-fluoro-3-nitrobenzaldehyde (150
1 and acetoacetic acid isopropyl ester (158■) and 3
Methyl amic acid (126 ml) was dissolved in isobutyl alcohol (1 ml) and heated under reflux overnight. The solvent was removed, the residue was subjected to chromatography, and both fractions eluted from a mixture of n-hexane and ethyl acetate were collected.
2,6-dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-dihydro-a-pyridine-3,5-
Dicarboxylic acid-3-feel ester-5-isobutyl ester rfl Jk L ta.

Physical property value IRυ″′ll″ (CHCj3): 345f1,11
495.1610°ax 1530.135(I NMRδppm(<l:DcJ+,): 7.8-7
．． 3 (m, 2H), 7.2-6.7 (m,
1B), 5.9 (brds, III), 5.17 (s,
IB) 4.81m+1)1), 3.4fi(s,”)l
) +2-21 (se6H) 1.20 (d, 3H), 1.
00(d,3H) Example 4 2-Fluocy-3-riIJIJ-<nuzaldehyde (159 rumors) and methyl 3-amic Inotonate (126
(1) and methyl acetoacetate (127) were heated under reflux for 8 hours in Impropatol (1 ml). The solvent was removed and the residue was subjected to silica gel chromatography.
- From both fractions eluted from a mixture of hexane and ethyl acetate, the target 2,6-dimethyl-4- (2', -fluoro-3' -// 6 cy) -1,4
-Dihythoroviridine-3,5-dicarboxylic acid dimethylpester was collected.

Physical property value knee 1R-1' LCHClg): 3450, 1695, 1
615゜aw 146(1,130O NMRδppm(CD(J,): 7.2-6.6(
m, 3B), s, 75 (brdlI, IH),
5.03 (s, IH), 3.52 (s, 6H).

2.20(8,61F) Example 5 2-Fluocr-5-nitropenzaldehyde (16
9n@) and methyl 3-amic a)y acid (126■)
and methyl acetoacetate <127r11 g,) were heated under reflux in Impropatol (1 ml) for 8 hours.

The solvent was removed and the residue was subjected to silica gel chromatography, and the desired 2,6-dimethyl-4-(2'-fluoron-5'- diphenyl) -1,4-dihydro pyridine-3,5-dicarboxylic acid dimethyl ester (
165■) was loaded.

Physical property value IRυ1' (CHCj, ): 3450, 1695, 16
10°ax 1470.135O NMRδppm (CDCj!,): 8.1~7. F
l (m, 2H), 7. l~s, s(m, 1B
), 5.90 (brds, 1 day), 5.15 (s.

1B), 3.48 (s, 611), 2.20 (s
, 6) 1) Example 6 2-Fluocr-3-21[I benzaldehyde (1
531+1i:) and methyl 3-amic o1-onate (
120■) Toacetoacetic acid-('2-n-buta-boxyethyl) ester (188■)
1 ml) and heated under reflux for 12 hours. melty 17
The target 2,6-dimethyl-4-(2'-
FluoroIj3/-nitrophenyl)-1,4-dihyde-a-pyridine-3,5-dicarboxylic acid-3-methyl ester-5(2n-p-a-boxethyl) ester (19sq
) was taken on board.

Physical property value knee IRu≦(CHCj, ): 345o, tsso, 5a1
o.

14fi0.1345 NMRJppm (CD(Js): 7.8~7.2
(m, 2H), 7.1~6.7(m, 111
), 6.2 (brds, IH), 5.10 (s, IH)
a, 0ff (t, 2H), 3.45 (s+, 3H), 3
．． 20 (t.

2H), 2.10 (s, 6B), '1.45 (m,
2H).

o, 92 (t, 3H) Continuation of page 1 @) Int, CI,' Identification symbol Internal serial number 0
Akira Yoshi Okamiya Akira Hino City Asahiga”

Claims (1)

[Claims] 1. A 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative represented by the following formula (1). λ Following formula 111] HO [In the formula, x, y, and z are as defined above. ] and the following formula CIII) CH
,C0CH,COO-B ・・・・・・・・・・・・・・・
...(III) An acetoacetate compound represented by [wherein B is the same as defined above] and the following formula (P/'3 CH, -C=CH-Coo -A...・・・・・・
・・・・・・・l'lV)NH. A method for producing a 1,4-dihyde 1j pyridine-3,5-dicarboxylic acid diester derivative represented by the following formula C1), which comprises reacting a 3-aminocrotonic acid ester compound represented by the following formula C1).